Serotonin is involved in numerous physiological processes, including
sleep,
thermoregulation,
learning and
memory,
pain, (social) behavior, and
biological rhythms. In less complex animals, such as some
invertebrates, serotonin regulates feeding and other processes. Despite its longstanding prominence in pharmaceutical advertising, the claim that low serotonin levels cause depression is not supported by scientific evidence.
Cellular effects Serotonin primarily acts through its receptors and its effects depend on which cells and tissues express these receptors. The rate-limiting step is hydride transfer from serotonin to the flavin cofactor. There follows oxidation by
aldehyde dehydrogenase (ALDH) to
5-hydroxyindoleacetic acid (), the
indole acetic-acid derivative. The latter is then excreted by the kidneys.
Receptors The
serotonin receptors are located on the
cell membrane of
nerve cells and other cell types in animals, and mediate the effects of serotonin as the
endogenous ligand and of a broad range of pharmaceutical and
psychedelic drugs. There are currently 14known serotonin receptors, including the serotonin
5-HT1 (
1A,
1B,
1D,
1E,
1F),
5-HT2 (
2A,
2B,
2C),
5-HT3,
5-HT4,
5-HT5 (
5A,
5B),
5-HT6, and
5-HT7 receptors. Except for the serotonin
5-HT3 receptor, a ligand-gated
ion channel, all other 5-HT receptors are
G-protein-coupled receptors (also called seven-transmembrane, or heptahelical receptors) that activate an
intracellular second messenger cascade. The 5-HT5B receptor is present in rodents but not in humans. In addition to the serotonin receptors, serotonin is an
agonist of the
trace amine-associated receptor 1 (TAAR1) in some species. It is a weak TAAR1
partial agonist in rats, but is inactive at the TAAR1 in mice and humans.
Termination Serotonergic action is terminated primarily via
uptake of 5-HT from the synapse. This is accomplished through the specific
monoamine transporter for 5-HT,
SERT, on the presynaptic neuron. Various agents can inhibit 5-HT reuptake, including
cocaine,
dextromethorphan (an
antitussive),
tricyclic antidepressants and
selective serotonin reuptake inhibitors (SSRIs). A 2006 study found that a significant portion of 5-HT's synaptic clearance is due to the selective activity of the
plasma membrane monoamine transporter (PMAT) which actively transports the molecule across the membrane and back into the presynaptic cell. In contrast to the high affinity of SERT, the PMAT has been identified as a low-affinity transporter, with an apparent
Km of 114 micromoles/l for serotonin, which is approximately 230 times higher than that of SERT. However, the PMAT, despite its relatively low serotonergic affinity, has a considerably higher transport "capacity" than SERT, "resulting in roughly comparable uptake efficiencies to SERT ... in heterologous expression systems." A similar process underlies the pancreatic release of insulin.
Nervous system s upwards to the whole cerebrum, and one collection next to the cerebellum that sends axons downward to the spinal cord. Slightly forward the upper serotonergic neurons is the
ventral tegmental area (VTA), which contains dopaminergic neurons. These neurons' axons then connect to the
nucleus accumbens,
hippocampus, and the
frontal cortex. Over the VTA is another collection of dopaminergic cells, the
substansia nigra, which send axons to the
striatum. |Serotonin system, contrasted with the
dopamine system The neurons of the
raphe nuclei are the principal source of 5-HT release in the brain. There are nine raphe nuclei, designated B1–B9, which contain the majority of serotonin-containing neurons (some scientists chose to group the
nuclei raphes lineares into one nucleus), all of which are located along the midline of the
brainstem, and centered on the
reticular formation. Axons from the neurons of the raphe nuclei form a
neurotransmitter system reaching almost every part of the central nervous system. Axons of neurons in the lower raphe nuclei terminate in the
cerebellum and
spinal cord, while the axons of the higher nuclei spread out in the entire brain. It is the dorsal part of the raphe nucleus that contains neurons projecting to the central nervous system. Serotonin-releasing neurons in this area receive input from a large number of areas, notably from
prefrontal cortex,
lateral habenula,
preoptic area,
substantia nigra and
amygdala. These neurons are thought to communicate the expectation of rewards in the near future, a quantity called state value in
reinforcement learning.
Ultrastructure and function The serotonin nuclei may also be divided into two main groups, the rostral and caudal containing three and four nuclei respectively. The rostral group consists of the caudal linear nuclei (B8), the dorsal raphe nuclei (B6 and B7) and the median raphe nuclei (B5, B8 and B9), that project into multiple cortical and subcortical structures. The caudal group consists of the nucleus raphe magnus (B3), raphe obscurus nucleus (B2), raphe pallidus nucleus (B1), and lateral medullary reticular formation, that project into the brainstem. The serotonergic pathway is involved in sensorimotor function, with pathways projecting both into cortical (Dorsal and Median Raphe Nuclei), subcortical, and spinal areas involved in motor activity. Pharmacological manipulation suggests that serotonergic activity increases with motor activity while firing rates of serotonergic neurons increase with intense visual stimuli. Animal models suggest that kainate signaling negatively regulates serotonin actions in the retina, with possible implications for the control of the visual system. The descending projections form a pathway that inhibits pain called the "descending inhibitory pathway" that may be relevant to a disorder such as fibromyalgia, migraine, and other pain disorders, and the efficacy of antidepressants in them. Serotonergic projections from the caudal nuclei are involved in regulating mood and emotion, and hypo- or hyper-serotonergic states may be involved in depression and sickness behavior.
Microanatomy Serotonin is released into the synapse, or space between neurons, and diffuses over a relatively wide gap (>20 nm) to activate
5-HT receptors located on the
dendrites, cell bodies, and
presynaptic terminals of adjacent neurons. When humans smell food, dopamine is released to
increase the appetite. But, unlike in worms, serotonin does not increase anticipatory behaviour in humans; instead, the serotonin released while consuming activates
5-HT2C receptors on dopamine-producing cells. This halts their dopamine release, and thereby serotonin decreases appetite. Drugs that block 5-HT2C receptors make the body unable to recognize when it is no longer hungry or otherwise in need of nutrients, and are associated with weight gain, especially in people with a low number of receptors. The expression of 5-HT2C receptors in the
hippocampus follows a
diurnal rhythm, just as the serotonin release in the
ventromedial nucleus, which is characterised by a peak at morning when the motivation to eat is strongest. In
macaques, alpha males have twice the level of serotonin in the brain as subordinate males and females (measured by the concentration of
5-HIAA in the
cerebrospinal fluid (CSF)). Dominance status and CSF serotonin levels appear to be positively correlated. When dominant males were removed from such groups, subordinate males begin competing for dominance. Once new dominance hierarchies were established, serotonin levels of the new dominant individuals also increased to double those in subordinate males and females. The reason why serotonin levels are only high in dominant males, but not dominant females has not yet been established. In humans, levels of 5-HT1A receptor inhibition in the brain show negative correlation with aggression, and a mutation in the gene that codes for the
5-HT2A receptor may double the risk of suicide for those with that genotype. Serotonin in the brain is not usually degraded after use, but is collected by serotonergic neurons through
serotonin transporters on their cell surfaces. Studies have revealed nearly 10% of total variance in anxiety-related personality depends on variations in the
description of where, when and how many serotonin transporters the neurons should deploy.
Outside the nervous system Digestive tract (emetic) Serotonin regulates gastrointestinal (GI) function. The gut is surrounded by
enterochromaffin cells, which release serotonin in response to food in the
lumen. This makes the gut contract around the food. Platelets in the
veins draining the gut collect excess serotonin. There are often serotonin abnormalities in gastrointestinal disorders such as constipation and irritable bowel syndrome. If irritants are present in the food, the enterochromaffin cells release more serotonin to make the gut move faster, i.e., to cause diarrhea, so the gut is emptied of the noxious substance. If serotonin is released in the blood faster than the platelets can absorb it, the level of free serotonin in the blood is increased. This activates
5-HT3 receptors in the
chemoreceptor trigger zone that stimulate
vomiting. Thus, drugs and toxins stimulate serotonin release from enterochromaffin cells in the gut wall which can induce emesis. The enterochromaffin cells not only react to bad food but are also very sensitive to
irradiation and
cancer chemotherapy. Drugs that
block 5HT3 are very effective in controlling the nausea and vomiting produced by cancer treatment, and are considered the gold standard for this purpose.
Lungs The
lung, including that of reptiles, contains specialized
epithelial cells that occur as solitary cells or as clusters called neuroepithelial bodies or bronchial Kulchitsky cells or alternatively
K cells. These are enterochromaffin cells that like those in the gut release serotonin.
Bone metabolism In mice and humans, alterations in serotonin levels and signalling have been shown to regulate bone mass. Mice that lack brain serotonin have
osteopenia, while mice that lack gut serotonin have high bone density. In humans, increased blood serotonin levels have been shown to be a significant negative predictor of low bone density. Serotonin can also be synthesized, albeit at very low levels, in the bone cells. It mediates its actions on bone cells using three different receptors. Through
5-HT1B receptors, it negatively regulates bone mass, while it does so positively through
5-HT2B receptors and
5-HT2C receptors. There is very delicate balance between physiological role of gut serotonin and its pathology. Increase in the extracellular content of serotonin results in a complex relay of signals in the
osteoblasts culminating in FoxO1/ Creb and ATF4 dependent transcriptional events. Following the 2008 findings that gut serotonin regulates bone mass, the mechanistic investigations into what regulates serotonin synthesis from the gut in the regulation of bone mass have started.
Piezo1 has been shown to sense RNA in the gut and relay this information through serotonin synthesis to the bone by acting as a sensor of single-stranded RNA (ssRNA) governing 5-HT production. Intestinal epithelium-specific deletion of mouse
Piezo1 profoundly disturbed gut peristalsis, impeded experimental colitis, and suppressed serum 5-HT levels. Because of systemic 5-HT deficiency, conditional knockout of
Piezo1 increased bone formation. Notably, fecal ssRNA was identified as a natural Piezo1 ligand, and ssRNA-stimulated 5-HT synthesis from the gut was evoked in a MyD88/TRIF-independent manner. Colonic infusion of RNase A suppressed gut motility and increased bone mass. These findings suggest gut ssRNA as a master determinant of systemic 5-HT levels, indicating the ssRNA-Piezo1 axis as a potential prophylactic target for treatment of bone and gut disorders. Studies in 2008, 2010 and 2019 have opened the potential for serotonin research to treat bone mass disorders.
Organ development Since serotonin signals resource availability it is not surprising that it affects organ development. Many human and animal studies have shown that nutrition in early life can influence, in adulthood, such things as body fatness, blood lipids, blood pressure,
atherosclerosis, behavior, learning, and longevity. Rodent experiment shows that neonatal exposure to SSRIs makes persistent changes in the serotonergic transmission of the brain resulting in behavioral changes, which are reversed by treatment with antidepressants. By treating normal and
knockout mice lacking the serotonin transporter with fluoxetine scientists showed that normal emotional reactions in adulthood, like a short latency to escape foot shocks and inclination to explore new environments were dependent on active serotonin transporters during the neonatal period. Human serotonin can also act as a
growth factor directly. Liver damage increases cellular expression of
5-HT2A and
5-HT2B receptors, mediating liver compensatory regrowth (see ) Serotonin present in the blood then stimulates cellular growth to repair liver damage. 5-HT2B receptors also activate
osteocytes, which build up bone However, serotonin also inhibits osteoblasts, through 5-HT1B receptors.
Cardiovascular growth factor Serotonin, in addition, evokes
endothelial nitric oxide synthase activation and stimulates, through a
5-HT1B receptor-mediated mechanism, the phosphorylation of p44/p42 mitogen-activated protein kinase activation in bovine aortic endothelial cell cultures. In blood, serotonin is collected from plasma by platelets, which store it. It is thus active wherever platelets bind in damaged tissue, as a vasoconstrictor to stop bleeding, and also as a fibrocyte mitotic (growth factor), to aid healing.
Adipose tissue Serotonin also regulates white and brown
adipose tissue function, and
adipocytes are capable of producing 5-HT separately from the gut. Serotonin increases
lipogenesis through
HTR2A in white adipose tissue, and suppressed
thermogenesis in brown adipose tissue via Htr3. ==Pharmacology==